Principles of Autoimmunity Flashcards
(35 cards)
What is autoimmunity?
- reaction against self antigens.
- diseases can be organ-specific or systemic
Can autoantibodies be found in healthy individuals?
- YES (particularly the aged).
* may be formed in response to release of cryptic (intracellular) antigens occurring during cell injury.
What are the 3 requirements of pathologic autoimmunity?
- presence of an autoimmune reaction.
- evidence that the reaction is NOT secondary (aka it is primary) to tissue damage, but instead is of primary importance in pathogenesis.
- absence of another, well-defined cause of the disease.
What cell type primarily drives autoimmune disorders?
- T CELLS and/or ANTIBODIES directed against self antigens.
What are some ORGAN SPECIFIC autoimmune diseases?
- autoimmune hemolytic anemia (antibody)
- MS (T cells)
- goodpastures (antibody)
- autoimmune thrombocytopenia (antibody)
- T1DM (T cells)
- myasthenia gravis (antibody)
- graves disease (antibody)
What are some SYSTEMIC autoimmune diseases?
- systemic lupus erythematosus (antibody)
- rheumatoid arthritis (T cells and antibody)
- sjogren syndrome (T cells)
- systemic sclerosis (scleroderma; T cells)
** From what does autoimmunity result?
- a breakdown in self-tolerance
What are the 2 general pathways of autoimmunity?
- susceptibility genes leading to failure of self-tolerance.
- environmental trigger (infections) activating self-reactive lymphocytes
What is immunologic tolerance?
- a state in which the individual is incapable of developing an immune response to a specific antigen.
*** What are the 2 mechanisms for SELF TOLERANCE?
- CENTRAL tolerance= occurs during lymphocyte maturation in the primary lymphoid organs; all cells pass through a stage in which encounter with an antigen leads to cell death, receptor editing, or anergy.
- PERIPHERAL tolerance= occurs when mature lymphocytes that recognize self antigens, become incapable of responding to that antigen, lose viability or are induced to die via apoptosis.
What are the 3 important events in the development of B and T lymphocytes?
- commitment of progenitor cells to the B or T cell lineage.
- Temporally ordered process of rearrangement of antigen receptor genes and expression of antigen receptor proteins.
- selection events that preserve cells that have produced correct antigen receptor proteins and elimination events to remove potentially dangerous cells.
* these developmental checkpoints ensure that all mature lymphocytes express functional receptors with useful (and not deleterious) specificities.
Where does central tolerance occur?
- Bone marrow (B lymphocytes)
2. Thymus (T lymphocytes)
What are the mechanisms of CENTRAL tolerance?
- double positive T cells with high affinity T cell receptor for self antigen are deleted (NEGATIVE selection) via apoptosis.
- clonal deletion is also operative in developing B cells= developing B cells (IgM+ IgD-) encounter membrane bound antigen in the bone marrow.
- clonal deletion is not foolproof bc many self antigens are still not expressed in the bone marrow and/or thymus.
At what stage of B cell maturation does negative selection (central tolerance) occur?
- IMMATURE B CELL (after pro- and pre-B cell development, but before mature B cell stage) in the BONE MARROW.
At what stage of T cell maturation does positive and negative selection occur?
- between DOUBLE POSITIVE and SINGLE POSITIVE (immature T cell) development in the THYMUS.
Is anergy a mechanism of central or peripheral tolerance?
- PERIPHERAL.
- It is defined as the prolonged or irreversible functional inactivation of lymphocyte or as a state of unresponsiveness to antigenic stimulation.
Where are almost all antigens in the body going to be expressed?
- medulla of the thymus
* aka where we are going to show all the self-antigens
What is the role of the thymus?
- clonal deletion
- development of multiple populations of cells responsible for maintaining peripheral tolerance (dendritic and T regulatory cells).
How do PERIPHERAL antigens that are not normally expressed in primary lymphoid organs get to those organs to participate in negative selection processes?
- AIRE (AutoImmune REgulator)= stimulates the expression of many “peripheral” self-antigens in the thymus (specifically medullary thymic epithelial cells (mTECs).
- AIRE is critical for deletion of immature self reactive T cells in the thymus.
What do mutations of AIRE cause?
- autoimmune polyendocrinopathy
May anergy occur if the antigen is presented to a T cell without the APC cell expressing CD80/86 (B7 1/2)?
- YES
* anergy is a TEMPORARY phenomenon and long term requires re-engagement.
How else can we create an anergic state? (aka maintain peripheral tolerance)
- CTLA-4= competes with CD28 for B7 binding. When CTLA-4 binds to B7 (CD80/86), the T cell receives a down regulatory signal.
- PD-1= ligands on dendritic cells
What are Foxp3-expressing CD4 T cells?
- T regulatory cells (Tregs). These cells suppress immune responses through numerous mechanisms: anti-inflammatory cytokines, direct cell-cell contact, or by modulating the activation of APCs.
What controls T cell activation?
- engagement with MHC
- CD28 (T cell) engagement with CD80/86 (B7; APC).
* leads to activation of immune response.
